The invention relates to a process for preparing discodermolide and analogues thereof, to novel compounds utilized in the process and to novel compounds prepared by the process.
The present invention relates to the area of synthetic methodology and, more particularly, to a process for preparing discodermolide and analogues thereof.

(+)-Discodermolide is a novel polyketide natural product that was isolated from extracts of the marine sponge Discodernolide dissoluta by researchers at the Harbor Branch Oceanographic Institution (HBOI) (Gunasekera S P, Gunasekera M, Longley R E, Schulte G K. Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge Discodernia dissolute. [published erratum appears in J. Org. Chem. 1991;56:1346]. J. Org. Chem. 1990;55:4912-15.). Discodermolide lacks obvious structural resemblance to paclitaxel, yet it shares with paclitaxel (the active substance in the drug Taxol) the ability to stabilize microtubules. In mechanism-based assays, discodermolide is more effective than paclitaxel. In fact, of the handful of compounds known to induce polymerization of purified tubulin, discodermolide is the most potent. However, microtubules, a major structural component in cells, are not simple equlibrium polymers of tubulin. They exist as regulated GTP-driven dynamic assemblies of heterodimers of a and P tubulin. Although the dynamics are relatively slow in interphase cells, upon entering mitosis, the rate of growing and shortening increases 20 to 100-foldxe2x80x94the average microtubule turns over half the tubulin subunits every ten seconds. This change in rate allows the cytoskeletal microtubule network to dismantle and a bipolar spindle-shaped array of microtubules to assemble. The spindle attaches to chromosomes and moves them apart. The response to complete suppression of microtubule dynamics in cells is death. However, mitotic cells are more sensitive and the tolerance threshold appears to be cell-type specific. Molecules like paclitaxel that bind with high affinity to microtubules disrupt the dynamics process in tumor cells with lethal results even when the ratio of bound drug to tubulin is very low. Discodermolide binds to tubulin competitively with paclitaxel. Since paclitaxel has proven to be useful in treating some cancers, other compounds of the same mechanistic class may have utility against hyperproliferative disorders.
Future development of discodermolide or structurally related analogues is hindered by the lack of a reliable natural source of the compound or a feasible synthetic route. Naturally occurring discodermolide is scarce and harvesting the producing organism presents logistical problems. Accordingly, there is an ever-growing need for improved syntheses which enable the preparation of commercially acceptable quantities of discodermolide and structurally related analogues.
WO 00/04865 discloses the preparation of intermediates for the synthesis of discodermolide and their polyhydroxy dienyl lactone derivatives for pharmaceutical use.
Agnew. Chem., Vol. 39, No. 2, pgs. 377-380 (2000) discloses the total synthesis of the antimicrotubule agent (+)-discodermolide using boron-mediated aldol reactions of chiral ketones.
Org. Lett., Vol. 1, No. 11, pgs. 1823-1826 (1999) discloses the gram-scale synthesis of (+)-discodermolide.
Diss. Abstr. Int., Vol. 60, No. 3, pg. 1087 (1999) discloses the total synthesis of (+)-miyakolide, (xe2x88x92)-discodermolide and (+)-discodermolide.
Tetrahedron Lett., Vol. 40, No. 30, pgs 5449-5453 (1999) discloses the synthesis of C1-C8 and C9-C24 fragments of (xe2x88x92)-discodermolide.
Diss. Abstr. Int., Vol. 59, No. 11, pg. 5854 (1999) discloses a total synthesis of (xe2x88x92)-discodermolide.
J. Org. Chem., Vol. 63, No. 22, pgs. 7885-7892 (1998) discloses the total synthesis of (+)-discodermolide.
WO 98/24429 discloses synthetic techniques and intermediates for polyhydroxy, dienyllactones and mimics thereof.
J. Am. Chem. Soc., Vol. 118, No. 45, pgs. 11054-11080 (1996) discloses the syntheses of discodermolides useful for investigating microtubule binding and stabilization.
J. Am. Chem. Soc., Vol. 117, No. 48, pgs. 12011-12012 (1995) discloses the total synthesis of (xe2x88x92)-discodermolide.
British Patent Application 2,280,677 discloses the total synthesis of discodermolide.
The present invention relates to a more practical synthesis of discodermolide and analogues thereof. In another embodiment, the instant invention relates to novel compounds useful in the preparation of discodermolide and analogues thereof. In a further embodiment, the instant invention relates to novel compounds which are prepared by the process of the instant invention.
The essence of the instant invention is the discovery of a more practical synthesis for discodermolide and analogues thereof. More particularly, it has been discovered that discodermolide and analogues thereof can be prepared by a three-step reaction as follows: 
where R1 is (C1-6) alkyl, benzyl or an acid labile hydroxyl protecting group; R2 is (C1-6) alkyl or benzyl; R3 is hydrogen, (C1-6) alkyl, benzyl, C(O)(C1-12) alkyl, C(O)Ph, C(O)O(C1-12) alkyl, C(O,Ph, C(O)NH(C1-12) alkyl, C(O)NHPh or an acid labile hydroxyl protecting group; R3xe2x80x3 is an acid labile hydroxyl protecting group; R4 is hydrogen or methyl; and X is O, NH, NCH3, S or CH2, with the proviso that when X is O and R3 is an acid labile hydroxyl protecting group in the compound of formula I, the xe2x80x9cxe2x80x94Xxe2x80x94R3xe2x80x9d moiety in the compound of formula V is xe2x80x94OH.
As to the individual steps, Step 1 involves the coupling of a ketone compound of formula I with an aldehyde compound of formula II via an aldol reaction to obtain a xcex2-hydroxyketone compound of formula III. The coupling is conveniently carried out with between 1 and 20, preferably between 5 and 15, equivalents of the ketone compound of formula I relative to the aldehyde compound of formula II. The coupling is conducted in the presence of: 1) a dialkylboron halide or triflate, preferably a chiral boron chloride or triflate, more preferably xcex2-chlorodiisopinocamphenylborane; 2) a base, preferably an amine, more preferably triethylamine; and 3) a polar organic solvent, preferably an ether, more preferably diethyl ether, at a temperature of between xe2x88x92100xc2x0 C. and 20xc2x0 C., preferably between xe2x88x9278xc2x0 C. and xe2x88x9220xc2x0 C., for a period of between 2 and 72 hours, preferably for 16 hours.
Step 2 concerns the reduction of the xcex2-hydroxyketone compound of formula III and, more particularly, the ketone group common to such compounds, to obtain a 1,3-diol compound of formula IV. The reduction is conducted in the presence of: 1) a ketone reducing agent, preferably a borohydride such as tetramethylammonium triacetoxyborohydride; 2) a polar organic solvent, preferably acetonitrile; and 3) a protic solvent, preferably a carboxylic acid, such as acetic acid, at a temperature of between xe2x88x9278xc2x0 C. and 20xc2x0 C., preferably between xe2x88x9240xc2x0 C. and xe2x88x9210xc2x0 C., for a period of between 2 and 72 hours, preferably for 16 hours.
As to Step 3, it involves the lactonization and deprotection of the acid labile hydroxyl protecting groups of a compound of formula IV to obtain a compound of formula V. The lactonization and deprotection reaction is conducted in the presence of: 1) a protic acid, preferably an aqueous protic acid solution, preferably an aqueous hydrogen halide solution, such as aqueous hydrogen chloride; and 2) a polar organic solvent, preferably a mixture of polar organic solvents, more preferably a mixture of an aliphatic alcohol and an ether, such as methanol and tetrahydrofuran, at a temperature of between xe2x88x9220xc2x0 C. and 40xc2x0 C., preferably between 20xc2x0 C. and 25xc2x0 C., for a period of 8 hours and 7 days, preferably between 16 and 72 hours, more preferably between 24 and 48 hours.
In another embodiment, the instant invention relates to the novel ketone compounds of formula I: 
where R1 is (C1-6) alkyl, benzyl, or an acid labile hydroxyl protecting group;
R2 is (C1-6) alkyl, or benzyl;
R3 is hydrogen, (C1-6) alkyl, benzyl, C(O)(C1-12) alkyl, C(O)Ph, C(O)O(C1-12)alkyl, C(O)OPh, C(O)NH(C1-12)alkyl, C(O)NHPh, or an acid labile hydroxyl protecting group;
R4 is hydrogen or methyl; and
X is O, NH, NCH3, S or CH2.
Preferred compounds are those of formula Ia: 
where each of R1xe2x80x2 and R2xe2x80x2 is (C1-6) alkyl;
X is O, or CH2; and
R3 and R4 are as defined above.
More preferred compounds are those of formula Ib: 
where R3xe2x80x2 is (C1-6)alkyl, C(O)(C1-12)alkyl, benzyl, C(O)O(C1-12)alkyl, or an acid labile hydroxy protecting group; and
R1xe2x80x2 and R2xe2x80x2 are as defined above.
Even more preferred compound are those of formula Ic: 
where R3xe2x80x3 is an acid labile hydroxyl protecting group.
In the above definitions: the term xe2x80x9c(C1-6) alkylxe2x80x9d as used herein refers to a straight or branched chain group consisting solely of carbon and hydrogen and having from 1 to 6 carbon atoms, whereas the term xe2x80x9c(C1-12) alkylxe2x80x9d as used herein refers to a straight or branched chain group consisting solely of carbon and hydrogen and having from 1 to 12 carbon atoms. Examples of xe2x80x9calkylxe2x80x9d groups include methyl, ethyl, propyl, butyl, pentyl, 3-methylpentyl, etc.
The term xe2x80x9cacid labile hydroxyl protecting groupsxe2x80x9d as used herein refers to any oxygen bound group that can be removed upon exposure to an acid. Numerous examples of these groups are known by those skilled in the art and can be found in Greene and Wuts, Protective Groups in Organic Synthesis, 2d edition, John Wiley and Sons, New York, 1991. Specific examples include, but are not limited to, t-butyldimethylsilyl, triethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, methoxymethyl, and tetrahydropyranyl.
In a further embodiment, the instant invention relates to a process for preparing the novel compounds of formula I. More particularly, the compounds of formula I may be prepared as depicted below: 
where R1, R2, R3, R4 and X are as defined above.
As to the individual steps, Step A involves the addition of a methyl or ethyl group to an aldehyde compound of formula VI to obtain an alcohol compound of formula VII. The addition is carried out in the presence of: 1) an organometallic reagent, preferably an alkyllithium or alkylmagnesium halide such as methylmagnesium bromide; and 2) a polar organic solvent, preferably an ether such as diethyl ether, at a temperature of between xe2x88x9278xc2x0 C. and 40xc2x0 C., preferably at xe2x88x9278xc2x0 C. and 0xc2x0 C., more preferably at about xe2x88x9240xc2x0 C., for a period of between 5 minutes and 24 hours, preferably between 30 minutes and 2 hours, more preferably for about 1 hour.
Step B involves the oxidation of an alcohol compound of formula VII to obtain the desired ketone compound of formula I. The oxidation is carried out in the presence of: 1) an oxidant, preferably a combination of dimethylsulfoxide and an activating agent, more preferably a combination of dimethylsulfoxide and sulfur trioxide complex with pyridine; 2) a base, preferably an organic base, more preferably a trialkylamine such as triethylamine; and 3) a polar organic solvent, preferably a chlorinated hydrocarbon such as dichloromethane. The oxidation is suitably carried out a temperature of between xe2x88x9278xc2x0 C. and 40xc2x0 C., preferably between 5xc2x0 C. and 20xc2x0 C., for a period of between 5 minutes and 24 hours, preferably between 1 hour and 12 hours, more preferably between 4 and 6 hours.
The aldehyde compounds of formulae II and VI are either known or may be prepared analogous to processes set forth in the literature for other structurally similar aldehydes.
In still another embodiment, the instant invention relates to the novel xcex2-hydroxyketone compounds of formula III and the novel 1,3-diol compounds of formula IV.
Although the product of each reaction described above may, if desired, be purified by conventional techniques such as chromatography or recrystallization (if a solid), the crude product of one reaction is advantageously employed in the following reaction without purification.
As is evident to those skilled in the art, compounds of formulae I and III-V contain asymmetric carbon atoms and, therefore, it should be understood that the individual stereoisomers are contemplated as being included within the scope of this invention.